Molecular insights into Mmpl3 lead to the development of novel indole-2-carboxamides as antitubercular agents?

Molecular Systems Design & Engineering Pub Date: 2022-03-02 DOI: 10.1039/D1ME00122A

Abstract

Tuberculosis (TB) is an air-borne infectious disease and is the leading cause of death among all infectious diseases globally. The current treatment regimen for TB is overtly long and patient non-compliance often leads to drug resistant TB resulting in a need to develop new drugs that will act via novel mechanisms. In this research work, we selected mycobacterial membrane protein Large 3 (MmpL3) as the drug target and indole-2-carboximide as our molecule of interest for further designing new molecules. A homology model was prepared for Mycobacterium tuberculosis MmpL3 from the crystal structure of Mycobacterium smegmatis MmpL3. A series of indoles which are known to be MmpL3 inhibitors were docked in the prepared protein and the binding site properties were identified. Based on that, 10 molecules were designed and synthesized and their antitubercular activities were evaluated. We identified four hits among which the highest potency candidate possessed a minimum inhibitory concentration (MIC) of 1.56 μM at 2 weeks. Finally, molecular dynamics simulation studies were done with 3b and a previously reported MmpL3 inhibitor to understand the intricacies of their binding in real time and to correlate the experimental findings with the simulation data.

Graphical abstract: Molecular insights into Mmpl3 lead to the development of novel indole-2-carboxamides as antitubercular agents
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